Open AccessIncreased FOXM 1 expression can stimulate DNA repair in normal hepatocytes in vivo but also increases nuclear foci associated with senescence
Author(s) -
Baranski O. A.,
Kalinichenko V. V.,
Adami G. R.
Publication year - 2015
Publication title -
cell proliferation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.647
H-Index - 74
eISSN - 1365-2184
pISSN - 0960-7722
DOI - 10.1111/cpr.12153
Subject(s) - foxm1 , senescence , dna damage , biology , dna repair , transcription factor , in vivo , microbiology and biotechnology , endogeny , dna , cell growth , cell , cancer research , gene , genetics , biochemistry
Objectives FOXM 1 is a transcription factor that has been shown to promote cell proliferation in many tissues during early development and high cell turnover tissues in adults. In a number of tumour cell lines, enrichment of FOXM 1 has been shown to reduce the DNA damage response ( DDR ) and induction of senescence by a range of DNA ‐damaging agents, suggesting a role for the protein in DNA repair. Endogenous FOXM 1 is expressed at detectable levels in hepatocytes of mice up to 2 weeks of age, but not in older mice. The aim of this investigation has been to better understand the role of the protein in DDR in normal cells in vivo . Materials and methods Mice with artificially prolonged elevated FOXM 1 expression in hepatocytes, were exposed to alkylating diethylnitrosamine. Results FOXM 1‐enriched mice had dampened DDR after treatment with this alkylating agent, which was consistent with observed increase in expression of genes involved in DNA repair. Paradoxically, mice with FOXM 1 expression, within weeks after exposure to the DNA ‐damaging agent, had increased levels of potentially senescent hepatocytes with large nuclear foci, containing 53 BP 1. Similarly, spontaneous accumulation of these cells seen with normal ageing in mice was increased with FOXM 1 enrichment. Conclusion Despite its known abilities to promote proliferation and DNA repair, and to reduce ROS , enrichment of FOXM 1, as with other oncoproteins, may cause increased persistent DNA lesions and/or senescence in normal murine hepatocytes.